Our long-term programmatic goal is to develop screening strategies to diagnose asymptomatic pancreaticcancer (PaC). Up to 80% of PaCs have hyperglycemia and diabetes (DM), which is evident many monthsprior to the cancer diagnosis and improves following resection of PaC. Conversely, older subjects with newonsetDM have a ~8 fold higher risk of having PaC compared to the general population. Recognition ofnew-onset DM as an early manifestation of PaC could lead to diagnosis of asymptomatic early stagePaC. In this proposal we take our strong and consistent clinical and epidemiological observations to thelaboratory to understand the pathogenesis of PaC-associated DM (PaCDM) and identify its biomarkers.Specific Aim 1: To determine if B-cell dysfunction is an early and key defect in PaCDM: DM occurs ininsulin resistant states when B-cells fail to compensate for impaired insulin action. The very high prevalenceof DM in PaC implies high rate of B-cell failure. We have developed a technique in humans to simultaneouslyassess B-cell function, insulin sensitivity, and hepatic insulin extraction using 3 radiolabeled glucose tracers.We have used this technique to study subjects with type 2 DM, impaired glucose tolerance and normalglucose tolerance. We will perform similar studies in PaC to determine if B-cell dysfunction is an early andkey defect in glucose metabolism in PaCDM. Specific Aim 2: To determine if adrenomedullin (AM) is themediator of PaCDM: AM is a 52 amino acid peptide hormone expressed in normal human islets that inhibitsinsulin exocytosis from B-cells. It is markedly overexpressed in PaC and its plasma levels are increased inPaCDM. We hypothesize thai AM is the mediator of B-cell dysfunction in PaC. In preliminary studies wehave been able to